When a drug is administered systemically to an individual either orally or by intravenous injection and the like, there are cases in which adverse side effects are observed in normal tissue other than the targeted lesion, thereby forcing modification or discontinuation of the treatment method. In addition, depending on the particular drug, there are some cases that it may also be difficult to maintain the concentration of a drug that allows that drug to be effective, and that the drug may be metabolized prior to being delivered to the target site.
In order to solve these problems, sophisticated pharmaceutical techniques and concepts have been introduced that attempt to optimize therapeutic efficacy by imparting a desirable drug concentration-time pattern at the target site of action by controlling the pharmacokinetics of the drug in the body or by selective delivery thereof, and extensive research is currently being conducted in this field. These techniques and concepts are collectively referred to as a drug delivery system (DDS), and have recently come to be viewed with particular importance from the viewpoint of delivering substances such as anti-cancer drugs, DNA or peptides to the site of a tumor, inflamed site or other lesion with greater safety and efficiency.
Specific examples of methods for deploying DDS that have been developed include methods utilizing drug carriers such as liposomes, emulsions or nanoparticles, methods containing drugs in high molecular weight carriers such as polymeric micelles, and methods covalently bonding drugs to synthetic polymers or naturally occurring polysaccharides. The development of DDS preparations makes it possible to achieve superior efficacy and reduced adverse side effects for compounds that have already been developed as drugs. In addition, the use of DDS is expected to revive drugs, for which development had been abandoned from the viewpoints of adverse side effect or other factors, for use as pharmaceuticals. However, various issues must still be addressed when attempting to use these systems at the practical level, and among these, avoidance of the body's foreign substance recognition system, increasing drug concentration in DDS drug carriers, and control of drug release rate are considered to be particularly important.
With respect to avoiding the body's foreign substance recognition system, coating the surface of liposomes and other drug carriers with a hydrophilic polymer such as polyethylene glycol has made it possible to prevent adsorption by plasma proteins and opsonin proteins and enhance stability in the blood, thereby avoiding capture in the liver and spleen by the reticuloendothelial system (RES). As a result, liposomes and polymeric micelles allow the obtaining of high blood retention levels following intravenous administration and are able passively accumulate in tumor tissue, inflamed sites and other tissues having increased vascular permeability, thereby enabling treatment to be carried out efficiently.
On the other hand, with respect to drug content in DDS drug carriers, a higher drug content makes it possible to reduce the amount of carrier required to deliver the required drug, and as a result thereof, is advantageous in terms of both therapeutic efficacy and pharmaceutical design (J. Med. Chem., 45, 4336-4343 (2002) (NPL1)). Nevertheless, there are limitations on the drug content of liposomes and polymeric micelles from the viewpoint of physical stability, and if the drug content is increased in polymer complex types of drug carriers, the increase has an effect on the properties of the water-soluble polymer and the water-solubility thereof ends up decreasing. As a result, since interactions with plasma components are no longer able to be inhibited and it is no longer possible to maintain retention in the blood, nearly all such carriers have a drug content of only several percent (CRIPS 5(2), 2-8 (2004) (NPL2). Research has been conducted with the goal of achieving both high drug content and superior blood retention, and DDS compounds are being developed that have a high drug content and superior blood retention.
In addition, with respect to drug release, a system in which a drug is stably incorporated or bound to a carrier in the blood and is then rapidly released after having arrived at diseased tissue is ideal from the viewpoints of reducing adverse side effects and enhancing therapeutic efficacy. Various types of environment-sensitive carriers, or in other words, drug carriers that undergo a change in their physical properties in response to an environmental change induced by a lesion or in response to a difference between the environments of normal tissue and the site of a lesion, are being examined in order to realize a higher level of drug release control.
For example, HPMA copolymer-doxorubicin (PK1) has been reported that couples doxorubicin to an HPMA polymer having a molecular weight of about 30,000 Da through a spacer. Although PK1 allows the drug to be released by cathepsin B, which is more highly expressed at the site of a tumor than normal tissue, the drug content thereof is only about 8.5%, preventing it from achieving a high drug content.
On the other hand, since the local pH at the site of a tumor, inflammation or other diseased site is lower than that of normal tissue, studies have been conducted that utilize this phenomenon for the purpose of allowing a drug to be released in response to the environment attributable to such a change in pH at the diseased site (Adv. Drug Delivery Rev., 56, 1023-1050 (2004) (NPL3); Biochim. Biophys. Acta., 1329(2), 291-320 (1997) (NPL4)).
In addition, polymer complexes responding to a low pH environment within cells (J. Controlled Release, 87, 33-47 (2003) (NPL5)) and polymeric micelles (Bioconjugate Chem., 16, 122-130 (2005) (NPL6); J. Controlled Release, 64, 143-153 (2000) (NPL7)) have been reported in which a drug is released in precise response to a low pH environment within endosomes after having been locally incorporated into individual cancer cells of a tumor via the endocytosis pathway. Moreover, biodegradable doxorubicin micelles (J. Controlled Release, 96, 273-283 (2004) (NPL8)) and adriamycin (Bioconjugate Chem., 18, 1131-1139 (2007) (NPL9)) have been reported that are designed to be selectively incorporated in cancer cells highly expressing folic acid receptors by coupling folic acid to PEG expressed on the surface of polymeric micelles. Moreover, attempts have also been made to increase blood retention, and polymeric micelles have been developed that satisfy all of the conditions of pH dependency of drug release, superior retention in the blood and high drug content (Japanese Patent No. 4791435 (PTL1); US Patent No. 2008/0248097 (PTL2)).
However, when treatment is performed using anti-cancer agents, although elimination of the cancer can be temporarily confirmed, currently developed anti-cancer agents are unable to completely eradicate all cancer cells, and cancer is known to recur and metastasize due to the survival of an extremely small number of cancer cells that have acquired resistance. In particular, these cancer cells that have acquired resistance have been reported to include self-replicating and pluripotent cells referred to as cancer stem cells (Nat. Med., 3, 730-737 (1997) (NPL10); Nat. Med., March 17(3), 313-319 (2011) (NPL11)). Cancer has been clearly demonstrated to occur in and progress from cancer stem cells in several types of cancer including acute myelogenous leukemia. Since the development of anti-cancer drugs targeted at reducing the size of solid tumors alone is inadequate for these cancers, there is a desire for the development of an anti-cancer agent that is capable of eradicating cancer stem cells.